Experimental Pharmacology of the Methylenedioxyindenes

Abstract

Calcium antagonists represent the most important addition to the therapeutic armamentarium for the treatment of cardiovascular diseases since the advent of the padrenergic receptor blocking drugs. Based on their cellular site of action, the calcium antagonists are broadly classified into two groups ( 13 1): the calcium channel blockers and the intracellular calcium antagonists. While the list of calcium channel blockers is expanding at a very rapid pace (Table I), that of intracellular calcium antagonists is relatively limited ( Table 2). Numerous recent reviews have been published on the calcium channel blockers (34,62,168), but only a few dealt with the intracellular calcium antagonists (62,13 l). While calcium channel blockers exert their pharmacological actions primarily by limiting calcium entry into cardiac or vascular smooth muscle cells, the intracellular calcium antagonists exert their actions by blocking intracelMar calcium receptors (e.g., troponin or calmodulin), preventing calcium mobilization from intracellular stores, facilitating calcium sequestration by intracellular organelles, enhancing calcium efflux from the cell, or interfering with the contractile proteins (1 3 1). The present review focuses on the methylenedioxyindenes (MDIs), a group of tertiary amine intracellular calcium antagonists developed in our laboratory (U.S. patents #4393226 and #4542153). The MDIs fulfill most of the criteria ( 13 I ) that qualify an agent to be classified primarily as an intracellular calcium antagonist. The MDIs inhibit the mobilization of calcium from the sarcoplasmic reticulum and preserve mitochondria1 structural and functional integrity against swelling and uncoupling of oxidative phosphorylation ( 132). DISCOVERY OF THE MDIsSerendipity and traditional pharmacological approaches contributed to the development of the MDIs. The MDIs were synthesized as intermediates (178) for the chemical synthesis of dibenzyloxyindanpropionic acids [DIPA (1 77)J (Fig. 1 ), in a research effort aimed at developing antiabortifacient prostaglandin FZa receptor antagonists, an endeavor that was ultimately successful (1 39). The intermediate MDIs

Examination of the Potential Antiilcer Activity of the Calcium Antagonist Propyl-Methylenedioxyindene

“…The higher of the two doses of pr-MDl was previously shown to exert only a modest 12 % inhibition of the bethanechol-induced titratable acidity and a 10% inhibition of the bethanechol-induced lowering of gastic pH [12]. Higher doses of pr-MDI were not exam ined for two reasons: first, the low doses of 10 and 30 mg/kg currently used were previously shown to inhibit gastric stress ulcers in rats [11]; second, higher doses of pr-MDI would result in cardiovascular depression [6] which would render any antiulcer effect at such doses of questionable therapeutic potential.…”

“…In an attempt to circumvent the complex ities and uncertainties of the gastrointestinal membrane calcium channels, we examined the potential antiulcer activity of propylmethylenedioxyindene (pr-MDI), an intra cellular-acting calcium antagonist [6] which inhibits calcium mobilization from the en doplasmic reticulum [7], This calcium antag onist inhibits intracellular calcium-mediated processes in vitro at concentrations of 10~5-10-4 mol/1 [6], and also blocks (cardiac) H2-receptors with a pA2 value of 6.46 (com pared with 6.10 for cimetidine) [8,9], and inhibitis H [-receptor-mediated (EC70 = 5 X 10-5 mol/1) and muscarinic-receptor-medi ated (EC70 = 10~4 mol/1) intestinal smooth muscle contraction [10]. Our previous find ings demonstrated the ability of pr-MDI to prevent the development of cold-restraint stress-induced gastric ulcers in rats in a dosedependent manner at doses (10-30 mg/kg, i.p.)…”